Phosphatidylinositol 3-kinase (PI3K), which is also known as phosphoinositol 3-kinase or phosphoinositide 3-kinase, is a lipid kinase capable of phosphorylating 3-hydroxyl group of an inositol ring and plays an important role in cell proliferation, survival, motility and the like (Nature 387: 673-6 (1997)).
Class I PI3Ks (PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ) are activated by receptor tyrosine kinase or G-protein coupled receptor (GPCR) to produce phosphatidylinositol 3,4,5-triphosphate (PIP3) and activate Akt. The activated Akt controls cell proliferation, survival, vascularization, etc. by phosphorylating TSC2, GSK3β, MDM2, FOXO, BAD and the like (Nature Rev. Cancer 5: 921-929 (2005)).
Class I PI3Ks are heterodimeric molecules composed of p110 catalytic subunits and regulatory subunits. They are further classified into Class IA and Class IB on their regulatory partner and regulation mechanism. Class IA enzymes are composed of five (5) different enzymes based regulatory subunits (p85α, p55α, p50α, p85β and p55γ) and three (3) different catalytic subunits (p110α, p110β and p110δ), and all of the catalytic subunits interact with all of the regulatory subunits to form various types of heterodimer. Class IA PI3Ks are generally activated in response to growth factor-stimulation of receptor tyrosine kinases, via interaction of the regulatory subunit SH2 domains with certain phospho-tyrosine residues of the activated receptor or adaptor proteins such as insulin receptor substrate-1 (IRS-1). Both p110α and p110β are mainly expressed in all cell types, whereas the expression of p110δ is more restricted to inflammatory cells including leukocytes and some epithelial cells (Curr. Opin. Pharmacol. 3(4): 426-434 (2003); Thromb Haemost 99: 279-285 (2008)). In contrast, the single Class IB enzymes consist of p120γ catalytic subunits that interact with p101 regulatory subunits (which is commonly referred to as “p110γ”; see Cell 89: 105-114, April 1997, etc.). Moreover, Class IB enzymes are activated in response to G-protein coupled receptor (GPCRs) and its expression appears to be limited to inflammatory cells, including leukocytes and macrophagocytes, and cardiomyocytes (Thromb Haemost 99: 279-285 (2008)).
It is known that overactivity of p110α, a catalytic subunit of PI3Kα, is found in colon cancer, breast cancer, brain tumor, gastric cancer, liver cancer, ovarian cancer, etc. (Acta Pharmacologica Sinica 33: 1441-1458 (2012)). Also, it has been reported that p110α regulates proliferation of smooth muscle cells and cytokine secretion in bronchial smooth muscle cells of patients with severe asthma (J Pharmacol Exp Ther. 337(2): 557-566 (2011)). It is also known to participate in conversion of fibroblast to myofibroblast by TGFβ1 in patients with idiopathic pulmonary fibrosis (PLoS ONE 6(10): e24663 (2011)). Further, it is observed that PI3K-Akt pathway are overactivated in cancers where phosphatase and tensin homolog (PTEN) that dephosphorylates PIP3 is inactivated or p110α is overactivated. Thus, a drug having an inhibitory activity against PI3K can be considered as promising cancer therapeutics because they can block PI3K-Akt pathway by inhibiting Akt activation to inhibit the proliferation, survival, vascularization of cancer cells (Crit Rev Oncog. 17(1): 69-95 (2012)). Furthermore, it has been reported that a drug having an anti-PI3K activity can be useful for treating asthma and chronic obstructive pulmonary disease (COPD) because they can mediate proliferative function of tracheal smooth muscle and prevent fibrogenesis which are causes of the airway remodeling in severe asthmatic patients (Nature Rev. Genet. 7: 606-619 (2006); Nature 441: 366-370 (2006); J Pharmacol Exp Ther. 337(2): 557-566 (2011); J Allergy Clin Immunol 116: 488-495 (2005)).
Both Class IA PI3K and Class IB PI3K enzymes play an important role in immune cells (Koyasu, Nature Immunology, 2003, 4, 313-319) and, thus, they are evaluated as therapeutic targets in inflammatory and allergic conditions. Recent studies have revealed that mice lacking PI3Kγ and PI3Kδ were able to survive, yet their inflammatory and allergic reactions were impaired (Ali et al, Nature, 2004, 431, (7011), 1007-1011). Also, it has been reported that anti-inflammatory and anti-fibrotic effects due to PI3K inhibition can control respiratory diseases such as asthma and COPD and is also useful in treating cardiovascular diseases (Prasad et al, Trends in Cardiovascular Medicine, 13, 206-212 (2003); Am J Physiol Lung Cell Mol Physiol 296: L210-L219, (2009)). Additionally, it has been revealed that Class I PI3K enzyme play an important role not only in basic processes of learning and memory but also in regulation of learning and judgment ability in intracellular signal transduction pathways (Nat Neurosci. 2011 Oct. 23; 14(11):1447-54). Accordingly, Class I PI3K enzyme inhibitors are expected to provide prophylactic and therapeutic benefits against cancer as well as a wide range of diseases including inflammatory disease.